Primary and Metastatic Brain Tumors: Page 4 of 5
Primary and Metastatic Brain Tumors: Page 4 of 5
Definitive Therapy: Brain Metastases
Surgery
Surgical approach for metastatic tumors. Most patients with brain metastases have a life expectancy of less than 6 months, but the majority who undergo resection of a metastatic lesion followed by irradiation will die of systemic rather than intracranial disease.
Excision of metastatic brain tumors is rarely curative, however, because microscopic cells may be left behind. Nevertheless, the reduced tumor burden becomes more amenable to adjuvant irradiation and/or chemotherapy.
Criteria. The decision whether to recommend surgery for metastatic brain tumors should be based on the following factors:
Extracranial oncologic status A comprehensive workup of the patient’s extracranial oncologic status is necessary. Extensive critical organ metastases preclude surgery in favor of palliative irradiation as the sole therapy. Brain surgery should not be performed in patients with limited expected survival (3 to 6 weeks) based on extracranial disease.
Number of metastases In general, only patients harboring a single metastasis are considered for resection. Occasionally, a large tumor will be removed in the presence of multiple smaller nodules if the edema and mass effect of this lesion are causing a substantial neurologic deficit that could be improved by tumor removal.
If brain metastasis is the presenting sign of systemic cancer and no clear primary source can be identified with routine staging, surgery may be required to establish a tissue diagnosis and plan further therapy.
In addition, surgical removal of a brain metastasis often reverses the neurologic deficits caused by compression of local structures by the tumor and reduces intracranial hypertension. After complete excision of a single brain metastasis, postoperative whole-brain radiotherapy improves control of neurologic disease but does not prolong survival.
Three studies have concluded that when multiple (up to three distinct locations) metastases are resected, either with or without radiotherapy, survival times are identical to those in patients with a surgically resected single metastasis and almost twice as long as those in patients treated by radiation therapy or radiosurgery alone. These studies suggest that a more aggressive surgical approach may be justified in patients with multiple brain metastases who have stable systemic disease.
Recurrence of solitary metastases. Up to 20% of single metastases may recur in long-term survivors. In these cases, a second operation may be warranted to remove the recurrent lesion and confirm the histologic diagnosis (ie, exclude radionecrosis).
The Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases that traditionally included age, KPS, the presence or absence of extracranial metastases (ECM), and the number of brain metastases (NBM) was updated to reflect the heterogeneity of significant prognostic factors determined by primary tumor type. GPA scores range from 0 to 4, in order of worst to best prognosis. Factors include age, KPS, ECM, and NBM for both NSCLC and SCLC; KPS and NBM for melanoma and renal cell carcinoma; age, KPS, and tumor subtype for breast cancer; and KPS alone for gastrointestinal cancer (Figure 5).
Radiotherapy
Radiation therapy for metastatic brain tumors. For symptomatic patients with brain metastases, median survival time is about 1 month if the patient remains untreated and 3 to 6 months if whole-brain radiation therapy is delivered, with no significant differences among various conventional radiotherapy fractionation schemes (20 Gy in 5 fractions, 30 Gy in 10 fractions, 40 Gy in 20 fractions). A more protracted schedule is used for patients who have limited or no evidence of systemic disease or for those who have undergone resection of a single brain metastasis, because these patients have the potential for long-term survival or even cure. The use of hypofractionated regimens is associated with an increased risk of neurologic toxicity.
The addition of the radiosensitizer motexafin gadolinium to whole-brain radiotherapy did not improve survival or time to neurologic disease progression in a randomized phase III trial. Subgroup analysis suggested a prolonged time to neurocognitive disease progression in patients with brain metastases from lung cancer, which was confirmed in a later study.
• Relief of neurologic symptoms—The major result of whole-brain radiation therapy is an improvement in neurologic symptoms, such as headache, motor loss, and impaired mentation. The overall response rate ranges from 70% to 90%. Unfortunately, symptomatic relief is not permanent, and symptoms recur with intracranial tumor progression.
• Multiple lesions—Patients with multiple lesions are generally treated with whole-brain radiation therapy alone. Re-treatment with a second course of whole-brain radiation therapy can provide further palliation for patients with progressive brain metastases (who have at least a 6-month or longer remission of symptoms after the initial course of cranial irradiation).
EORTC 22952 showed that adjuvant whole-brain radiation therapy decreases intracranial relapses and neurologic deaths but does not have an impact on survival or functional independence. Three hundred fifty-nine patients with one to three brain metastases underwent gross total resection or radiosurgery and were then randomly assigned to adjuvant whole-brain radiation therapy or observation. The median time to decline in performance status to more than 2 was 10 months after observation and 9.5 months after whole-brain radiation therapy, and overall survival was similar in both arms, at 10.7 months and 10.9 months, respectively.
• Concomitant corticosteroid therapy—Because the radiographic and clinical responses to whole-brain irradiation take several weeks, patients with significant mass effect should be treated with corticosteroids during whole-brain radiation therapy. Dexamethasone (16 mg/d) is started before therapy, and the dose may be tapered as tolerated during treatment. Occasionally, higher doses are necessary to ameliorate neurologic symptoms. However, most patients can be safely tapered off corticosteroids at the completion of whole-brain radiotherapy.
Radiosurgery for metastatic brain tumors
In patients with one to three brain metastases, aggressive local therapy (surgical resection or radiosurgery) produces superior survival and quality of life compared with whole-brain radiation therapy alone. Radiosurgery may be the optimal choice for elderly patients at greater risk for surgical morbidity. Radiosurgery has been used as sole therapy, as a boost to whole-brain radiation therapy, or for recurrent lesions in patients with brain metastases. Radiosurgery has the advantage of delivering effective focal treatment, usually in a single dose, without irradiating the normal brain. Radiosurgery of brain metastases less than 1 cm achieves 1- and 2-year local tumor control rates of 86% and 78%, respectively, significantly better than rates of 56% and 24%, respectively, for lesions greater than 1 cm. It is particularly useful for patients who have one to three lesions, each less than 4 cm in diameter. Patients with numerous lesions are not good candidates for radiosurgery because some of the ports may overlap, and more importantly, these patients likely harbor other microscopic lesions in the brain that are not being treated effectively with such focal therapy.
Brain metastases are particularly amenable to treatment with radiosurgery. Metastatic tumors do not infiltrate the brain and tend to have well-circumscribed borders; therefore, they can be targeted effectively with highly focused irradiation techniques that maintain a sharp delineation between the enhancing tumor seen on neuroimaging and normal brain. Furthermore, radiosurgery does not have the operative morbidity that may be associated with resection of a brain metastasis. Consequently, it can be used safely in many patients who are not surgical candidates, and it can even treat lesions in surgically unapproachable locations such as the brain stem.
Radiosurgery can achieve crude local tumor control rates of 73% to 98% over a median follow-up periodof 5 to 26 months. Radiosurgery was initially used as a boost after treatment with whole-brain radiotherapy. Three randomized trials have reported on the value of radiosurgery in addition to whole-brain radiotherapy for patients with multiple brain metastases. Although all three studies show a local tumor control advantage and an improvement in quality-of-life endpoints with the addition of a radiosurgical boost, none shows a statistical advantage in survival. For patients with multiple brain metastases, adding radiosurgery to whole-brain radiotherapy only offers an improved neurologic quality of life with no impact on survival.
A prospective, randomized RTOG trial compared whole-brain radiotherapy alone vs whole-brain radiotherapy plus radiosurgery in patients with one to three metastases. Although there was no statistical improvement in overall survival in the two arms of the trial, a subset analysis showed improved survival for those patients with a single lesion. Local tumor control, neurologic function, and corticosteroid doses were improved in patients with a single lesion treated with radiosurgery.
Radiosurgery is often considered an alternative to standard surgical resection, and accumulating evidence suggests they are largely equivalent for smaller lesions (< 2 cm), with some important nuances tailored to individual patient situations. Most retrospective studies suggest that the two techniques produce similar results; however, some reports indicate that surgery offers improved local tumor control, whereas others suggest that radiosurgery is superior.
Increasingly, radiosurgery is being used as the sole initial therapy for patients with one to three brain metastases. A prospective randomized trial compared radiosurgery with or without whole-brain radiotherapy in patients with one to four brain metastases. Results were similar to those of the phase III trial of surgical resection of a single brain metastasis with or without radiotherapy: improved local tumor control but no survival benefit. Therefore, whole-brain radiotherapy reduced CNS relapse but had no impact on survival.
Median survival from the time of radiosurgery is 6 to 15 months, and some patients can live for years without recurrence. Most patients exhibit clinical improvement and decreased corticosteroid requirement after radiosurgery, and only 11% to 25% of patients eventually die of neurologic causes.
Chemotherapy
Metastatic brain tumors. Chemotherapy usually has a limited role in the treatment of brain metastases and has not proved to be effective as adjuvant therapy after irradiation or surgery. However, it may have some efficacy in patients with recurrent brain metastases who are not eligible for further whole-brain radiation therapy or stereotactic radiosurgery. In addition, chemotherapy has proved active in patients with asymptomatic brain metastases (discovered on screening neuroimaging) who are scheduled to receive chemotherapy for their systemic disease. We have seen patients with brain metastases from a variety of primary tumors respond in this situation. A recent phase III trial of chemotherapy with early vs delayed whole-brain radiotherapy in NSCLC patients with brain metastases showed an identical intracranial response rate and survival. Thus, systemic chemotherapy had some efficacy against brain metastases.
A recently completed phase II trial of temozolomide (75 mg/m2/d) and concurrent whole-brain radiotherapy (40 Gy in 20 fractions) vs whole-brain radiotherapy alone demonstrated improved response rates and neurologic improvement in the combined-modality arm. In addition, there is growing recognition that systemic chemotherapy, including targeted agents, can be effective against brain metastases when the drugs are selected based on the primary tumor. Capecitabine (Xeloda), used primarily with lapatinib, is effective against brain metastases from HER2-positive breast cancer. High-dose methotrexate has activity against a number of primary tumors. Temozolomide has activity against recurrent brain metastases, particularly from NSCLC and melanoma.
Erlotinib has efficacy against brain metastases from lung cancer with the appropriate EGFR mutations.